This project focuses on novel cytomegalovirus (CMV)-encoded immunomodulators and host defense pathways with which they intersect during initial stages of infection to affect outcomes in both immunocompetent and immunodeficient hosts. Human CMV remains the single most important vaccine preventable cause of congenital disease as well as a significant pathogen in individuals with immune deficit. Modulation of host innate and adaptive immunity contributes to increased disease risk. Myeloid lineage cells are important targets of viral escape and exploitation tactics, starting at the initial encounter and proceeding through latency. Murine CMV provides a tractable model yielding mechanistic insights into pathogenesis relevant to human CMV and host defense strategies broadly relevant to many human pathogens. The host defense value of programmed necrotic death has recently emerged along with the fascinating observation that extrinsic programmed cell death pathways are dispensable for core aspects of the virus-host interaction, including immune control of viral infection. In the next period, we will specifically investigate the contribution of extrinsic death pathways in monocyte-derived cell function. The contribution programmed cell death pathways, as well as inflammation spawned by these pathways, will be dissected in three substantive and interlaced directions: Specific Aim 1 Host control of viral infection in the absence of caspase 8-regulated death pathways. (1.a) Determine the role of caspase 8 and RIP3-regulated pathways to monocyte function. (1.b) Assess the impact of inflammatory monocyte suppression of antiviral T cell immunity. (1.c) Investigate cell death pathways control of viral dissemination by patrolling monocytes. Specific Aim 2 Viral control of apoptotic and programmed necrotic cell death pathways. (2.a) Differentiation of cell types subjected to extrinsic apoptosis or programmed necrosis. (2.b) Assess the regulation of cell death pathways in endothelial cells and monocytes. Specific Aim 3 Defining the DAI-RIP3 pathway of programmed necrosis. (3.a) Determine the role of DAI as a pathogen sensor of infection via dsDNA. (3.b) Characterize DAI-RIP3 complex-dependent death. (3.c) Differentiate RIP1-RIP3 from DAI-RIP3 programmed necrosis in host defense. (3.d) Evaluate candidate RIP3 kinase inhibitors